Diabetes mellitus is a disease characterized by physiologic and anatomic abnormalities in many organs, due to vascular abnormalities. However, the most prominent feature of the disease is disturbed glucose metabolism, resulting in hyperglycemia. Diabetes mellitus is usually divided into two major categories: insulin-dependent diabetes mellitus (Type I diabetes), which usually develops in childhood or adolescence and these patients are prone to ketosis and acidosis. The second category of patients (Type lI diabetes) are not insulin dependent and usually manage with diet and oral hypoglycemic therapy. The annual incidence of Type I diabetes ranges from 10 cases/100.000 persons for non-white males to 16 cases/100.000 persons for white males in the United States, with equal incidence between males and females. The prevalence of Type I diabetes for all ages in the United States population is 160 cases/100.000 persons, with a slightly earlier onset for females with peak age of onset at 10-12 years than for males with peak age of onset at 18 years. Genetic background plays a major role in the development of the disease, with 40% concordance for Type I diabetes exhibited by identical twins and increased incidence among family members. Genes associated with increased susceptability to Type I diabetes reside near the major histocompatibility complex on chromosome 6, with more than 90% of persons with Type I diabetes featuring DR3 or DR4 haplotypes or both. Likewise, siblings sharing DR3 or DR4 haplotypes from both parents more often than random develop Type I diabetes (1).
The onset of symptoms in Type I diabetes is usually acute and frequently follows an antecedant vital infection which might be the trigger to a process leading to destruction of the beta cells secondary to autoimmune insulitis. When beta cell destruction reaches the critical point, the patient's reduced insulin levels lead to hyperglycemia with the typical symptomatology of Type I diabetes. At diagnosis approximately 70% of patients with Type I diabetes have antibodies to islet cell cytoplasm i.e. antigens or to components of the islet cell surface. Approximately 15% of patients with Type I diabetes may also show other autoimmune features, such as hypothyroidism, Graves' disease, Addison's disease, myasthenia gravis and pernicious anemia (2). Autopsies of cases with Type I diabetes show a typical lymphocytic infiltration in the pancreatic islets (3).
Treatment of Type I diabetes at present is not satisfactory and the disease leads to serious life-threatening complications that can be only partly overcome with adequate control of insulin levels, which is usually difficult to accomplish in patients with juvenile onset. In addition to the acute diabetic syndrome, chronic manifestations lead to severe arteriosclerosis with microadenopathy affecting the eye with possible early blindness. One in 20 of all Type I diabetes patients becomes blind; about 40% of Type I diabetes develop renal failure, resulting in chronic hemodialisis and/or the need for renal transplantation (4-7). Severe neuropathic changes are also typical for Type I diabetes with many functional disorders associated with sensory, sympathetic and para-sympathetic nerves. Cranial nerve, as well as peripheral nerve, may be involved. Treatment of neuropathy remains unsatisfactory, despite normal control of glucose levels with adequate insulin therapy.
Strokes are twice as frequent, myocardial infarctions are 2-5 times as frequent and cardiovascular accidents are 5-10 times more frequent in patients with Type I diabetes than among non-diabetic counterparts. The prognosis of patients with Type I diabetes who survive acute myocardial infarction is 3 times more grave compared to non-diabetics who survive acute infarction and the same is true for other vascular complications. Severe and uncontrollable arterosclerosis may also be associated with a variety of etiologies involving abnormalities in platelets, clotting factors and lipid carriers, such as HGL levels, as well as uncontrolled diabetes (1).
In view of the autoimmune nature of the disease, cyclosporine A has been suggested as a possible treatment of choice soon after the clinical manifestations of Type I diabetes with some encouraging results (8). Although complete and partial remission have been reported, randomized double-blind clinical trials are needed to assess the long-term effectiveness and safety of cyclosporine and other immunosuppressive modalities early in the course of IDDM.
The invention is further illustrated by the following experiments:
In order to study the effect of treatment regimens in connection with diabetes the experimental model with non-obese diabetic (NOD) mice has been commonly used. See the experimental part. Drugs counteracting lymphocytic infiltration of the pancreatic islets with subsequent degenerative changes, overt diabetes, manifesting hyperglycaemia, glycosuria, ketosis and weight loss, with an absolute requirement for insulin after the development of hyperglycaemia, are here and further on in connection with the invention defined as anti-diabetic drugs.
Quinoline-3-carboxamide compounds have been suggested as pharmaceuticals. The compounds have comprised the structure given in formula I below, optionally with substituents for the hydrogen atoms shown (H.sup.1-9, where H.sup.9 is part of X.sub.1 or X.sub.2 as shown in (b) below) and, where appropriate, salts of the compounds: ##STR2##
This formula is a collective formula for the tautomeric structures II-IV. ##STR3##
In formula I-IV:
(a) ----- represents that there are two conjugated double bonds between the atoms comprised by the dashed line (only formula I). PA1 (b) X.sub.1 and X.sub.2 are separately selected from an oxygen atom or an NH.sup.9 group that possibly is substituted, said X.sub.1 and X.sub.2 being bound by a single bond to the ring when attached to H.sup.7 or H.sup.8 and by a double bond when not bound to H.sup.7 or H.sup.8. PA1 (c) H.sup.1-9 are hydrogens, with the provision that H.sup.9 is only present when at least one of X.sub.1 and X.sub.2 is the NH.sup.9 group. PA1 (d) H.sup.7 and H.sup.8 are hydrogens that are attached to different atoms selected among X.sub.1, X.sub.2 and the nitrogen atom in the quinoline ring said X.sub.1 and X.sub.2 being bound by a single bond to the ring when attached to H.sup.7 or H.sup.8 and by a double bond when not bound to H.sup.7 or H.sup.8.
The substituents that are to replace H.sup.1-9 may, according to the prior art, comprise any substituent that gives compounds that can be isolated. See for instance Indian Journal of Chemistry Vol 17B (1979) 488-90 (anti-inflammatory properties), U.S. Pat. No. 3,960,868 (=GB 1,467,061, analgesic, anticonceptive, anti-inflammatory and anti-allergic properties), U.S. Pat. Nos. 4,547,511 and 4,738,971 (enhancing cell-mediated immunity), WO 9015052 (=U.S. Ser. No. 651,234, filed May 31, 1990) immunomodulator), U.S. Pat. No. 4,107,310 (analgetics) and JP 68023948 (bacteriocides). U.S. patents and patent applications given above are hereby incorporated by reference. In general it can be stated that many of the compounds comprising structure I are classified as immune modulators with individual effects spanning the spectra from suppression to stimulation of the immune system. The specific effect achieved depends on the substituents.
One of the most important compounds with formula I are the 1,2-dihydro-hydroquinoline-3-carboxamides, particularly N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxa mide (Linomide.RTM.), i.e. structures I and lI with a substituent for H.sup.1 that equals phenyl, for H.sup.2 that equals methyl, for H.sup.8 that equals methyl (attached to the nitrogen atom of the quinoline ring), with no substituents for H.sup.3-7, with H.sup.7 attached to X.sub.1, and with each of X.sub.1 and X.sub.2 equaling an oxygen atom. The compound has double bonds between positions 3 and 4 and between position 2 and X.sub.2.
The scientific experimentation with Linomide.RTM. has shown that Linomide has multiple immunological activities. It has thus been found that Linomide.RTM. increases the proliferative response to T and B cell mitogens (8), enhances antibody production (9) and augments NK cell activity (10, 11). Moreover, its immunostimulating and immunoregulating properties may be useful in the treatment of tumors (12) and systemic lupus erythematosis (13, 14) as suggested in U.S. Pat. Nos. 4,547,511 and 4,738,971.